The long term goal of these studies is to analyze the genetic mechanisms by which aneuploidy disrupts normal processes of development. Many types of studies of this problem are difficult or impossible in humans; however, an animal model system for studies of aneuploidy has been developed. The current proposal utilizes the trisomy (Ts) 16 mouse, which shares a genetic basis and many phenotypic manifestations with a specific human trisomy, Ts21, or Down syndrome (DS). As the most frequent live-born autosonal aneuploidy and the leading genetic cause of mental retardation, DS is a major health problem. Only a subset of the information present on chromosome 21 (HSA 21) (less than 25%) need be present in triplicate in order to produce a DS phenotype. Four of the genes from this DS region of HSA 21 have been mapped in the mouse, and all are clustered on mouse chromosome 16 (MMU 16). In addition to the genetic similarity between Ts16 and DS, examination of mice with Ts16 has revealed a number of developmental, neurochemical, neuropathological, and immunological correlates. Therefore, the Ts16 mouse has been proposed as an animal model of DS. The specific goal of this work is to characterize and compare the genetic compositions of the DS regions of mouse and human. This will be accomplished by determining the locations of genes already known to reside on MMU 16; by generating new genetic markers of MMU 16 and localizing them on high resolution genetic and cytologic maps of the chromosome; and by comparing the locations in the two species of mouse sequences which hybridize to HSA 21, and human sequences which hybridize to MMU 16. A detailed map of MMU 16 will also be useful in characterizing translocations of MMU 16 which are being generated in an effort to produce mice trisomic only for the DS region. Mapping will be accomplished in mice using backcrosses between different subspecies of Mus musculus which exhibit a high degree of genetic variation at the DNA level, and in humans by analysis of pedigrees and somatic cell hybrids; by the construction of somatic cell hybrids segregating translocations or subchromosomal fragments of MMU 16; and by in situ hybridization. New markers of MMU 16 are being generated currently using a highly repetitive mouse DNA sequence to screen an MMU 16-specific clone library.